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In this study, the functions and threats of Suraha Tal Wetland are identified by the stated preference method and weightage is given according to their rank. The objective of the study is to determine the total economic value of Suraha Tal Wetland. The direct value can be drawn from the market price and from a survey of the stakeholders. Suraha Tal Wetland is also famous for the presence of the Jai Prakash Narayan Birds Sanctuary, which makes it a biodiversity-enriched area. The indirect value has been drawn from a review of the literature on Suraha Tal Wetland and the relevance of this literature is justified through the comprehensive meta-analysis (CMA) software. The total valuation of the wetland has been calculated. The paper concludes with suggestions for a few management strategies for better wetland management.

Introduction: Disparities in health-related quality of life (HRQOL) have been inadequately studied in patients with glomerular disease. The aim of this study was to identify relationships among race/ethnicity, socioeconomic status, disease severity, and HRQOL in an ethnically and racially diverse cohort of patients with glomerular disease. Methods: Cure Glomerulonephropathy (CureGN) is a multinational cohort study of patients with biopsy-proven glomerular disease. Associations between race/ethnicity and HRQOL were determined by the following: (1) missed school or work due to kidney disease and (2) responses to Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaires. We adjusted for demographics, socioeconomic status, and disease characteristics using multivariable logistic and linear regression. Results: Black and Hispanic participants had worse socioeconomic status and more severe glomerular disease than white or Asian participants. Black adults missed work or school most frequently due to kidney disease (30 vs. 16–23% in the other 3 groups, p = 0.04), and had the worst self-reported global physical health (median score 44.1 vs. 48.0–48.2, p < 0.001) and fatigue (53.8 vs. 48.5–51.1, p = 0.002), compared to other racial/ethnic groups. However, these findings were not statistically significant with adjustment for socioeconomic status and disease severity, both of which were strongly associated with HRQOL in adults. Among children, disease severity but not race/ethnicity or socioeconomic status was associated with HRQOL. Conclusions: Among patients with glomerular disease enrolled in CureGN, the worse HRQOL reported by black adults was attributable to lower socioeconomic status and more severe glomerular disease. No racial/ethnic differences in HRQOL were observed in children.

Vernacular architecture in India conveys challenges of its climatic and social characteristics. With modernization, and with a greater ease of construction, a reduction in human labor, and the apparent robustness of contemporary construction techniques, architects are increasingly uncertain about vernacular architecture. This chapter emphasizes the features of the vernacular architecture of tropical India through case studies, specifically Kerala in southern India due to its rich culture and climatic challenges. Several modern case studies designed by various pioneering architects like Laurie Baker and Nari Gandhi that integrate the knowledge of the traditional architecture of tropical India through the learning from indigenous pre-modern examples as well as global trends have been studied. This chapter elucidates Baker's and Gandhi's consideration of vernacular architecture within their practice of sustainable building design and finally invites policy makers, planners, and architects to incorporate this knowledge into their policies and work.

With the broader introduction of genomic medicine in research and clinical care, an increasing number of persons are offered genetic testing. Many factors, including genetic literacy, may impact the utilization of genetic results by patients and their families. We developed a rapid, self‐administered measure of genetic literacy, called Genetic Literacy Fast Test (GeneLiFT). We next evaluated the association of GeneLiFT scores with the comprehension of limitations of genomic medicine in participants undergoing genetic testing in the NIH‐sponsored eMERGE III study at Columbia University Irving Medical Center, New York. All participants underwent genetic screening for variants in 74 actionable genes associated with adult‐onset disorders. A diverse cohort of 724 participants completed the survey (60% women, 45% less than 40 years old, and 53% self‐reported White non‐Hispanic ancestry). The GeneLiFT was validated using known group differences based on education, health literacy, and numeracy, and with questions assessing genetic knowledge. GeneLiFT identified multiple standard genetics terms, that is, jargon, not recognized by more than 50% of participants (including actionability and pathogenicity). Low genetic literacy, identified in 210 participants (29%), was significantly associated with poor understanding of the limitations of genetic testing (p‐values

Purpose The purpose of this study was to estimate the overall survival (OS) in real-world clinical practice in patients with metastatic breast cancer (MBC) and visceral metastases (liver or lung) treated in the third-line setting with eribulin, gemcitabine or capecitabine overall and in the major clinical categories of MBC (TNBC, HR+/HER2−, and HER2+). Methods A retrospective, observational study was conducted with de-identified patient electronic health records from the Cancer Treatment Centers of America (CTCA). Patients with a diagnosis of metastatic breast with lung or liver metastases, and treated with eribulin, gemcitabine, or capecitabine as third-line therapy were included in the analysis. Landmark survival was calculated as percentage of patients alive at 6, 12, 24, and 36 months. Overall survival was compared between treatment arms within TNBC and HR+/HER2− using log-rank analysis. Cox regression analyses was performed to estimate hazard ratios for comparison of treatments within TNBC and HR+/HER2− subtype. Results 443 patients with liver or lung metastases received third-line therapy with eribulin (n = 229), gemcitabine (n = 134), or capecitabine (n = 80). Eribulin patients had a higher percentage of patients alive at all landmark timepoints vs. gemcitabine, and a higher percentage of patients alive until 36 months vs. capecitabine. Median survival times showed that overall, and within the TNBC and HR+/HER2− subtype, patients receiving eribulin had a numerically higher median overall survival. Conclusions This real-world evidence study is consistent with randomized clinical trial data and demonstrates consistency of eribulin effectiveness in MBC patients with lung or liver metastases overall and in TNBC and HR+/HER2− disease.

Introduction Glomerular diseases are characterized by variable disease activity over many years. We aimed to analyze the relationship between clinical disease activity and duration of glomerular disease. Methods Disease activity in adults with chronic minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy (IgAN; first diagnostic biopsy >5 years before enrollment; Of Longstanding Disease [OLD] cohort, n = 256) followed at Columbia University Medical Center (CUMC), was compared with disease activity of an internal and external cohort of patients with first diagnostic biopsy, Graphical abstract

Introduction Lenvatinib has become the most commonly prescribed first-line (1L) agent for the treatment of radioactive iodine-refractory differentiated thyroid cancer (RAI-r DTC) since its approval in 2015. With no real-world studies describing clinical outcomes of 1L lenvatinib and subsequent therapy, the current study aimed to assess treatment sequencing and related clinical outcomes in patients treated with 1L lenvatinib in the USA Methods We conducted a multisite, retrospective chart review of US patients with a diagnosis of RAI-r DTC who had initiated 1L therapy with lenvatinib from January 1, 2016 through May 31, 2017 with follow-up through October 17, 2018. Physicians completed electronic case report forms for two patient cohorts: patients still receiving 1L lenvatinib (cohort 1) and those who had initiated second-line (2L) therapy prior to data cutoff (cohort 2). Real-world objective response rate (ORR) was assessed for both cohorts. Progression-free survival (PFS) and overall survival (OS) were assessed for cohort 2. Results A total of 252 patients met the study criteria with 71 in cohort 1 and 181 in cohort 2. Patients were predominantly female, had papillary DTC, and had lung metastases. The ORR was 64.8% for cohort 1 and 53.6% for cohort 2. In cohort 2, median PFS from 1L lenvatinib initiation was 14.0 months (95% CI 12.7–15.0). Second-line treatments included sorafenib (49.7%), cabozantinib (19.3%), and other targeted/chemotherapy/immuno-oncology agents. The ORR in 2L therapy was 15.5%. For cohort 2, the 12-, 18-, and 24-month OS from initiation of 1L lenvatinib was 92.8%, 81.5%, and 66.9%, respectively. Conclusions In this first real-world examination of clinical effectiveness of 1L lenvatinib and subsequent therapy among patients in the US, the results demonstrated that treatment with 1L lenvatinib followed by another 2L therapy may deliver a clinical benefit, thus allowing a number of potential 2L options following 1L lenvatinib for patients with RAI-r DTC.

Background: Ordering and delivering chemotherapy is complex, impacting patient and caregiver quality of life. Metastatic breast cancer (mBC) patients receive intravenous chemotherapy with variable administration times and patient satisfaction may differ by session length. We investigated common chemotherapy agents for mBC through a time and motion analysis. Methods: We conducted a prospective, observational time-and-motion study of adult females with mBC receiving ≥ 2nd-line eribulin, vinorelbine (VI), or gemcitabine (GC) at a large community oncology clinic. An observer documented times events occurred (Table). Patients completed a satisfaction survey adapted from Agency for Healthcare Research and Quality’s cancer care survey and the Cancer Therapy Satisfaction Questionnaire. Event times were compared using t-test. Spearman’s rank correlation was used to test correlations between time and satisfaction. Results: 17 patients (11 eribulin, 6 VI/GC) comprising 31 observations (20 eribulin, 11 VI/GC) were included in the preliminary analysis. Patients were 65 years on average, 71% white, and 94% post-menopausal; all were HER-2-. Mean years since mBC diagnosis was lower for eribulin than VI/GC patients (1.7 vs 5.0, p All observationsEribulin Vinorelbine/ GemcitabineP value * Citation Format: Lee Schwartzberg, Debanjana Chatterjee, Russel Knoth, Sarah N Gibbs, K Hamzah Ahmed, Michael S Broder, Irina Yermilov. A time-and-motion study of chemotherapy administration in metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-15-13.

The Church of the Mother of God at Studenica Monastery in Serbia was estab- lished by the medieval Serbian ruler and founder of his own dynasty, Stefan Nemanja (r. 1169–1196).1 The church is finely proportioned. Sophisticated treatment of wall surfaces additionally enriches the high-quality construc- tion in stone (figure 10.1). Nicely carved architectural sculpture enlivens the church exterior while extensive fresco decoration adorns the interior walls. The building is a single-nave structure, with a dominant square-based domical core and a tripartite sanctuary, typical for Byzantine-rite churches (figure 10.2). Architecturally and structurally speaking, this design is essentially a condensed form of a typical Middle Byzantine church, known as an atrophied Greek-cross church.2 In such churches, as in Studenica church, the lateral arms of the cross are reduced to narrow barrel vaults. Thus, these vaults effectively become mas- sive arches that project from structural piers; the same piers that carry trans- versal arches, which support the domical core of the structure. Part 2 Lighting Sacred Spaces Chapter 10 Modeling the Sunlight Illumination of the Church at Studenica Monastery In: Natural Light in Medieval Churches, Series: East Central and Eastern Europe in the Middle Ages, 450-1450, Volume 88 Volume Editors: Vladimir Ivanovici and Alice Isabella Sullivan https://brill.com/display/title/63611

Purpose: Recruitment of participants from diverse backgrounds is crucial to the generalizability of genetic research, but has proven challenging. We retrospectively evaluated recruitment methods used for a study on return of genetic results. Methods: The costs of study design, development, and participant enrollment were calculated, and the characteristics of the participants enrolled through the seven recruitment methods were examined. Results: A total of 1118 participants provided consent, a blood sample, and questionnaire data. The estimated cost across recruitment methods ranged from $579 to $1666 per participant and required a large recruitment team. Recruitment methods using flyers and staff networks were the most cost-efficient and resulted in the highest completion rate. Targeted sampling that emphasized the importance of Latino/a participation, utilization of translated materials, and in-person recruitments contributed to enrolling a demographically diverse sample. Conclusions: Although all methods were deployed in the same hospital or neighborhood and shared the same staff, each recruitment method was different in terms of cost and characteristics of the enrolled participants, suggesting the importance of carefully choosing the recruitment methods based on the desired composition of the final study sample. This analysis provides information about the effectiveness and cost of different methods to recruit adults for genetic research.

Introduction Little is known about real-world use of small molecule kinase inhibitors (SMKI) for advanced thyroid cancer in the United States. This study examined prescribing patterns of SMKI agents recommended by the National Comprehensive Cancer Center (NCCN). Methods This retrospective study used a national health insurance database to identify patients diagnosed with thyroid cancer during 1/1/2006–6/30/2016 and with prescription claims for NCCN-recommended SMKI during 1/1/2010–5/31/2016 whose first claim date was the index date. Inclusion also required continuous enrollment in a health plan for 3 months pre-index (baseline) and ≥ 1 month post-index (follow-up) with no claims for SMKI during baseline. Lines of therapy (LOT) were defined by the date of SMKI claims and days of drug supply. Median time to SMKI discontinuation in each LOT was estimated by Kaplan–Meier method. Results The study included 217 patients. During follow-up (mean duration 499.0 days), 35.5% of patients (n = 77) received a second or later LOT; among patients with ≥ 12 months follow-up after first LOT (LOT1) initiation, 53.1% (n = 60) received a second or later LOT. Median treatment duration was 5.0 months for LOT1 and 5.1 months for LOT2. Over the entire follow-up period (2010–2016), sorafenib was the most common regimen in LOT1 (36.9% of patients) and LOT2 (24.7%) followed by sunitinib and levantinib (13.4% each) in LOT1 and sunitinib (19.5%) in LOT2. Starting in 2015, the year lenvatinib was approved for differentiated thyroid cancer, lenvatinib was the most common first-line regimen among patients initiating LOT1 in 2015 (43.4%) and 2016 (66.7%). Conclusion Sorafenib was the most common first-line agent during 2010–2014 but was supplanted by lenvatinib starting in 2015. Approximately 36–53% of patients received a second-line treatment. Median treatment duration results suggested potential benefit of SMKI in second-line therapy. SMKI treatment after first-line failure may be considered for appropriately selected patients. Funding Eisai, Inc. (Woodcliff Lake, NJ).

BACKGROUND: Exome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adults, including chronic kidney disease, which affects more than 1 in 10 persons globally. METHODS: We conducted exome sequencing and diagnostic analysis in two cohorts totaling 3315 patients with chronic kidney disease. We assessed the diagnostic yield and, among the patients for whom detailed clinical data were available, the clinical implications of diagnostic and other medically relevant findings. RESULTS: In all, 3037 patients (91.6%) were over 21 years of age, and 1179 (35.6%) were of self-identified non-European ancestry. We detected diagnostic variants in 307 of the 3315 patients (9.3%), encompassing 66 different monogenic disorders. Of the disorders detected, 39 (59%) were found in only a single patient. Diagnostic variants were detected across all clinically defined categories, including congenital or cystic renal disease (127 of 531 patients [23.9%]) and nephropathy of unknown origin (48 of 281 patients [17.1%]). Of the 2187 patients assessed, 34 (1.6%) had genetic findings for medically actionable disorders that, although unrelated to their nephropathy, would also lead to subspecialty referral and inform renal management. CONCLUSIONS: Exome sequencing in a combined cohort of more than 3000 patients with chronic kidney disease yielded a genetic diagnosis in just under 10% of cases. (Funded by the National Institutes of Health and others.)

Early adolescence is a critical risk period for initiation of substance use. Internal assets (IAs), which are individual qualities guiding positive choices, and adverse childhood experiences (ACEs) are important protective and risk factors, respectively, against substance use. The purpose of this study is to investigate whether IAs modify associations between ACEs and early initiation of alcohol and marijuana use.Data were from 9th and 11th graders who completed the 2013 Minnesota Student Survey (n = 79,339). Students reported on experiences of abuse, household dysfunction, and substance use. Multivariable logistic regressions examined associations between different types of ACEs and substance use. Interactions between IAs and ACEs were added to models to test effect modification. For significant interactions, main effects models were re-estimated at different percentiles of IAs.IAs moderated associations of both abuse and household dysfunction with early initiation of marijuana (p.003) and alcohol (p =.007) for females but not for males. For females with low IAs, odds of early initiation of marijuana were approximately twice as high as students without any ACEs. A similar pattern was detected for females' initiation of alcohol use. No effect modification was detected for IAs and experiencing only abuse or household dysfunction on initiation.Special attention should be paid to improving IAs among girls who have already experienced ACEs. Future research should examine protective factors that buffer the effects of ACEs for boys.

Background: In order to gain a deeper understanding of the clinical, molecular and immune parameters involved in multiple myeloma (MM) disease initiation, progression and response to treatment, the Multiple Myleoma Research Foundation (MMRF) and its partners launched the CureCloud Research Initiative (NCT03657251), a Direct-to-Patient (DTP) effort aimed at enrolling 5,000 individuals from whom comprehensive molecular and immune analyses are generated from blood specimens and the resulting data aggregated with the correlating clinical information. Methods: To support the molecular characterization of liquid biopsies for CureCloud, a set of myeloma-specific blood-based approaches were developed. The first of such assays is a hybrid selection panel that captures 70 commonly altered MM and Clonal Hematopoiesis of Indeterminate Potential (CHIP) genes detecting somatic variants present in a patient's circulating-free DNA (cfDNA). This MM-70 assay was thoroughly validated to >90% sensitivity for events at 1% variant allele frequency with a specificity of Results: 580 subjects were enrolled to the study at abstract submission, including 127 smolderers, 173 newly diagnosed and 265 relapsed participants. 430 cases have been analyzed on the MM-70 assay. A mean cfDNA amount of 31 ng was recovered for input. Mean raw coverage depth of 176,000x was attained, with a mean duplex depth of 1271 (517-2406). 417 cases passed the minimum CLIA validation thresholds. Some of the most frequently mutated genes observed were in the MAPK, DNA repair, epigenetic, cell cycle, and NF-kappaB pathways in agreement with MM retrospective genomic research studies performed on bone marrow aspirates. Of interest, CHIP mutations were detected in a large proportion of cases (174) with their prevalence increasing with age (Figure 1A). 117 of patients had only one CHIP mutation while 57 had two or more with the same genomic loci were recurrently mutated in DNMT3A, TP53, ASXL1, and PPM1D. No significant differences in CHIP were observed between smoldering and overt myeloma subjects (Figure 1B). Interestingly, a greater (>0.1) CHIP Variant Allelic Fraction (VAF) was seen in individuals with higher risk genomic alterations (Figure 1C). Conclusion: This genomic characterization of one of the largest cohorts to date of individuals with myeloma and precursor conditions using a cfDNA-based liquid biopsy assay was able to recapitulate known myeloma-specific mutations and reinforced the importance of CHIP alterations in MM. CHIP mutations are indeed frequent in myeloma, increase with age, and higher burden might be related to disease aggressiveness. Figure 1 Figure 1. Disclosures Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

Aim: To examine the effectiveness of eribulin mesylate for metastatic breast cancer post cyclin-dependent kinase inhibitor (CDKi) 4/6 therapy. Materials & methods: US community oncologists reviewed charts of patients who had received eribulin from 3 February 2015 to 31 December 2017 after prior CDKi 4/6 therapy and detailed their clinical/treatment history, clinical outcomes (lesion measurements, progression, death) and toxicity. Results: Four patient cohorts were created according to eribulin line of therapy: second line, third line, per US label and fourth line with objective response rates/clinical benefit rates of 42.2%/58.7%, 26.1%/42.3%, 26.7%/54.1% and 17.9%/46.4%, respectively. Median progression-free survival/6-month progression-free survival (79.5% of all patients censored) by cohort was: 9.7 months/77.3%, 10.3 months/71.3%, not reached/70.4% and 4.0 months/0.0%, respectively. Overall occurrence of neutropenia = 23.5%, febrile neutropenia = 1.3%, peripheral neuropathy = 10.1% and diarrhea = 11.1%. Conclusion: Clinical outcome and adverse event rates were similar to those in clinical trials and other observational studies. Longer follow-up is required to confirm these findings.

The purpose of this study was to estimate the overall survival (OS) in real-world clinical practice in patients with metastatic breast cancer (MBC) and visceral metastases (liver or lung) treated in the third-line setting with eribulin, gemcitabine or capecitabine overall and in the major clinical categories of MBC (TNBC, HR+/HER2-, and HER2+).A retrospective, observational study was conducted with de-identified patient electronic health records from the Cancer Treatment Centers of America (CTCA). Patients with a diagnosis of metastatic breast with lung or liver metastases, and treated with eribulin, gemcitabine, or capecitabine as third-line therapy were included in the analysis. Landmark survival was calculated as percentage of patients alive at 6, 12, 24, and 36 months. Overall survival was compared between treatment arms within TNBC and HR+/HER2- using log-rank analysis. Cox regression analyses was performed to estimate hazard ratios for comparison of treatments within TNBC and HR+/HER2- subtype.443 patients with liver or lung metastases received third-line therapy with eribulin (n = 229), gemcitabine (n = 134), or capecitabine (n = 80). Eribulin patients had a higher percentage of patients alive at all landmark timepoints vs. gemcitabine, and a higher percentage of patients alive until 36 months vs. capecitabine. Median survival times showed that overall, and within the TNBC and HR+/HER2- subtype, patients receiving eribulin had a numerically higher median overall survival.This real-world evidence study is consistent with randomized clinical trial data and demonstrates consistency of eribulin effectiveness in MBC patients with lung or liver metastases overall and in TNBC and HR+/HER2- disease.

HIV infection is marked by phenotypic and functional alterations of immune cells. Different studies have shown both numerical and functional deterioration of dendritic cells in HIV-1-infected patients. In this study, we report an increase of inflammatory 6-sulfo LacNAc dendritic cells (slanDCs) that are more activated and produce higher amounts of interleukin (IL)-1β during HIV-1 infection as compared with healthy controls. IL-1β plays a regulatory role in chronic inflammatory disorders. Therefore, our findings might reveal a compensatory regulatory function of slanDCs during HIV-1 infection.

To function optimally, human blood natural killer (NK) cells need to communicate with other immune cells. Previously, it has been shown that NK cells communicate with 6-sulfo LacNAc dendritic cells (slanDCs), which are able to stimulate NK cells in vitro. In this study, we investigated how slanDCs regulate the level of NK cell activation. The secretion of interleukin (IL)-1β by slanDCs during coculture with NK cells increased as a result of signaling via intercellular adhesion molecule-1 on slanDCs following its interaction with lymphocyte function-associated antigen-1 on NK cells. IL-1β induced the expression of Fas receptor (CD95) on NK cells. The binding of Fas ligand (CD178) to CD95 induced the apoptosis of activated NK cells. Moreover, IL-1β also induced increased cyclooxygenase-2 expression in slanDCs, which in turn enabled the cells to secrete prostaglandin (PG)-E2. Consequently, PGE2 acted as a suppressing agent, tuning down the activation level of NK cells. In summary, IL-1β limits the level of NK cell activation by inducing apoptosis and suppression as a homeostatic regulatory function.

Rationale & Objectives Glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A (IgA) nephropathy, share clinical presentations, yet result from multiple biological mechanisms. Challenges to identifying underlying mechanisms, biomarkers, and new therapies include the rarity of each diagnosis and slow progression, often requiring decades to measure the effectiveness of interventions to prevent end-stage kidney disease (ESKD) or death. Study Design Multicenter prospective cohort study. Setting & Participants Cure Glomerulonephropathy (CureGN) will enroll 2,400 children and adults with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (including IgA vasculitis) and a first diagnostic kidney biopsy within 5 years. Patients with ESKD and those with secondary causes of glomerular disease are excluded. Exposures Clinical data, including medical history, medications, family history, and patient-reported outcomes, are obtained, along with a digital archive of kidney biopsy images and blood and urine specimens at study visits aligned with clinical care 1 to 4 times per year. Outcomes Patients are followed up for changes in estimated glomerular filtration rate, disease activity, ESKD, and death and for nonrenal complications of disease and treatment, including infection, malignancy, cardiovascular, and thromboembolic events. Analytical Approach The study design supports multiple longitudinal analyses leveraging the diverse data domains of CureGN and its ancillary program. At 2,400 patients and an average of 2 years' initial follow-up, CureGN has 80% power to detect an HR of 1.4 to 1.9 for proteinuria remission and a mean difference of 2.1 to 3.0mL/min/1.73m2 in estimated glomerular filtration rate per year. Limitations Current follow-up can only detect large differences in ESKD and death outcomes. Conclusions Study infrastructure will support a broad range of scientific approaches to identify mechanistically distinct subgroups, identify accurate biomarkers of disease activity and progression, delineate disease-specific treatment targets, and inform future therapeutic trials. CureGN is expected to be among the largest prospective studies of children and adults with glomerular disease, with a broad goal to lessen disease burden and improve outcomes.

Youth who experience homelessness have worse health and well-being than housed youth. Internal assets, including social competency and positive self-identity, are factors that promote healthy development. This study compared internal assets between homeless and housed youth, and examined whether connectedness with parents moderates the association between homelessness and internal assets. Using data from a large population-based survey of middle- and high-school aged youth, we found that homelessness was associated with lower levels of internal assets. However, having high connectedness with a parent significantly predicted the strength of these assets, suggesting opportunities to promote health equity among homeless youth.

There is scant literature describing the effect of glomerular disease on health-related quality of life (HRQOL). The Cure Glomerulonephropathy study (CureGN) is an international longitudinal cohort study of children and adults with four primary glomerular diseases (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy). HRQOL is systematically assessed using items from the Patient-Reported Outcomes Measurement Informative System (PROMIS). We assessed the relationship between HRQOL and demographic and clinical variables in 478 children and 1115 adults at the time of enrollment into CureGN. Domains measured by PROMIS items included global assessments of health, mobility, anxiety, fatigue, and sleep impairment, as well as a derived composite measure incorporating all measured domains. Multivariable models were created that explained 7 to 32% of variance in HRQOL. Patient-reported edema consistently had the strongest and most robust association with each measured domain of HRQOL in multivariable analysis (adjusted β [95% CI] for composite PROMIS score in children, -5.2 [-7.1 to -3.4]; for composite PROMIS score in adults, -6.1 [-7.4 to -4.9]). Female sex, weight (particularly obesity), and estimated glomerular filtration rate were also associated with some, but not all, domains of HRQOL. Primary diagnosis, disease duration, and exposure to immunosuppression were not associated with HRQOL after adjustment. Sensitivity analyses and interaction testing demonstrated no significant association between disease duration or immunosuppression and any measured domain of HRQOL. Thus, patient-reported edema has a consistent negative association with HRQOL in patients with primary glomerular diseases, with substantially greater impact than other demographic and clinical variables.

BackgroundThe life course perspective suggests a pathway may exist among maternal exposure to stressful life events prior to conception (PSLEs), infant birth weight and subsequent offspring health, whereby PSLEs are part of a 'chains-of-risk' that set children on a certain health pathway. No prior study has examined the link between PSLEs and offspring health in a nationally representative sample of US mothers and their children. We used longitudinal, nationally representative data to evaluate the relation between maternal exposure to PSLEs and subsequent measures of infant and toddler health, taking both maternal and obstetric characteristics into account.MethodsWe examined 6900 mother-child dyads participating in 2 waves of the nationally representative Early Childhood Longitudinal Study-Birth Cohort (n=6900). Infant and toddler health outcomes assessed at 9 and 24 months included overall health status, special healthcare needs and severe health conditions. Adjusted path analyses examined associations between PSLEs, birth weight and child health outcomes.ResultsIn adjusted analyses, PSLEs increased the risk for very low birth weight (VLBW

Background Cardiac allograft vasculopathy (CAV) has been associated with graft-infiltrating B cells, although their characteristics are still unclear. In this study we examined the frequency, localization and reactivity profile of graft-infiltrating B cells to determine their contribution to the pathophysiology of CAV. Methods B cells, plasma cells and macrophages were examined by immunohistochemistry in 56 allografts with CAV, 49 native failed hearts and 25 autopsy specimens. A total of 102 B-cell clones were immortalized directly from the infiltrates of 3 fresh cardiac samples with CAV. Their secreted antibodies were assessed using enzyme-linked immunoassay and flow cytometry. Results B-cell infiltration was observed around coronary arteries in 93% of allograft explants with CAV. Comparatively, intragraft B cells were less frequent and less dense in the intraventricular myocardium from where routine biopsies are obtained. Plasma cells and macrophages were also detected in 85% and 95% of explants, respectively. Remarkably, B-cell infiltrates were not associated with circulating donor-specific antibodies (DSA) or prior episodes of antibody-mediated rejection (AMR). Among all B-cell clones generated from 3 explants with CAV, a majority secreted natural antibodies reactive to multiple autoantigens and apoptotic cells, a characteristic of innate B cells. Conclusions Our study reveals a high frequency of infiltrating B cells around the coronary arteries of allografts with CAV, independent of DSA or AMR. These cells are enriched for innate B cells with a polyreactive profile. The findings shift the focus from conventional DSA-producing B cells to the potentially pathogenic polyreactive B cells in the development of clinical CAV.

Introduction: Obesity contributes significantly to cardiovascular disease (CVD) risk and weight management is associated with CVD risk reduction. Lorcaserin, a selective 5HT 2C receptor agonist, is indicated as an adjunct to a reduced-calorie diet and increase physical activity for weight management in adults with obesity (BMI≥30) and overweight (BMI 27-29.9 and ≥1 weight-related comorbidity). This analysis used the Framingham 10-year CVD risk to examine the impact of lorcaserin treatment on CVD risk and risk reduction. Method: Pooled data from two randomized, double-blind studies (BLOOM & BLOSSOM) investigating the efficacy of lorcaserin vs. placebo among non-diabetic patients with overweight or obesity, were used in this analysis. Framingham CVD risk was calculated for those whose lipid values were available at baseline and at one year. A Framingham CVD risk of Results: A total of 5,658 patients were evaluated, 51% treated with LOR. Among the LOR-treated patients, 43% achieved ≥5% weight loss at week 12 (compared to 19% treated with PBO). At one year, more patients in the LOR cohort had reduced CVD risk (from high to low risk, 21% vs. 15%, respectively). The regression analysis showed LOR-treated patients were 34% more likely to have low CVD risk (p Conclusion: The analysis suggests that patients treated with LOR are more likely to have low CVD risk at one year than those treated with PBO. The effect is magnified if patients have ≥5% weight loss at 12 weeks.

Introduction: Obesity is a risk factor for cardiovascular disease (CVD) and even modest weight loss can contribute to its reduction. Lorcaserin, a selective 5HT 2C receptor agonist, is indicated as an adjunct to a reduced-calorie diet and increased physical activity in adults with obesity (BMI≥30 kg/m 2 ) or overweight (BMI 27-29.9 kg/m 2 and at least 1 weight-related comorbidity). Using the 2013 ACC/AHA 10-year CVD risk assessment pooled cohort equation, we examined risk change in patients with metabolic syndrome or type 2 diabetes (T2DM) undergoing treatment with lorcaserin or placebo for weight loss. Methods: We identified patients with metabolic syndrome or T2DM in three randomized, double-blind studies (BLOOM, BLOSSOM, BLOOM-DM) examining the efficacy and safety of lorcaserin 10 mg bid (LOR) vs. placebo (PBO) at one year of treatment. Only patients with lipid values at baseline and one year were included. Once selected, patients were further stratified by weight loss at week 12 of treatment (≥5% vs. 5% was classified as high risk, and a 0.5% change in risk over one year was defined as clinically relevant. CVD risk reduction by cohorts, overall and by gender, was compared. Results: Overall, 43% LOR (n=449/1056) and 20% PBO (n=207/1041) patients had > 5% weight reduction at week 12 (p Conclusion: The analysis suggests that patients with overweight or obesity and metabolic syndrome/T2DM at risk for CVD, and treated with LOR, experienced a significant CVD risk reduction at one year vs PBO, most notably among men. LOR can effectively reduce weight, which is associated with improvements in CVD risk.

Background Pre-transplant sensitization is a limiting factor in solid-organ transplantation. In heart transplants, ventricular assist device (VAD) implantation has been associated with sensitization to human leukocyte antigens (HLA). The effect of VAD on non-HLA antibodies is unclear. We have previously shown that polyreactive natural antibodies (Nabs) contribute to pre-sensitization in kidney allograft recipients. Here we assessed generation of Nabs after VAD implantation in pre-transplant sera and examined their contribution to cardiac allograft outcome. Methods IgM and IgG Nabs were tested in pre-transplant serum samples collected from 206 orthotopic heart transplant recipients, including 128 patients with VAD (VAD patients) and 78 patients without VAD (no-VAD patients). Nabs were assessed by testing serum reactivity to apoptotic cells by flow cytometry and to the generic oxidized epitope, malondialdehyde, by enzyme-linked immunosorbent assay. Results No difference was observed in serum levels of IgM Nabs between VAD and no-VAD patients. However, serum IgG Nabs levels were significantly increased in VAD compared with no-VAD patients. This increase was likely due to the presence of the VAD, as revealed by lower serum IgG Nabs levels before implantation. Elevated pre-transplant IgG Nabs level was associated with development of primary graft dysfunction (PGD). Conclusions Our study demonstrates that VAD support elicits IgG Nabs reactive to apoptotic cells and oxidized epitopes. These findings further support broad and non-specific B-cell activation by VAD, resulting in IgG sensitization. Moreover, the association of serum IgG Nabs levels with development of PGD suggests a possible role for these antibodies in the inflammatory reaction accompanying this complication.

Recruitment of participants from diverse backgrounds is crucial to the generalizability of genetic research, but has proven challenging. We retrospectively evaluated recruitment methods used for a study on return of genetic results.The costs of study design, development, and participant enrollment were calculated, and the characteristics of the participants enrolled through the seven recruitment methods were examined.A total of 1118 participants provided consent, a blood sample, and questionnaire data. The estimated cost across recruitment methods ranged from $579 to $1666 per participant and required a large recruitment team. Recruitment methods using flyers and staff networks were the most cost-efficient and resulted in the highest completion rate. Targeted sampling that emphasized the importance of Latino/a participation, utilization of translated materials, and in-person recruitments contributed to enrolling a demographically diverse sample.Although all methods were deployed in the same hospital or neighborhood and shared the same staff, each recruitment method was different in terms of cost and characteristics of the enrolled participants, suggesting the importance of carefully choosing the recruitment methods based on the desired composition of the final study sample. This analysis provides information about the effectiveness and cost of different methods to recruit adults for genetic research.

Background Pooled analyses from 2 phase III trials of patients (pts) with metastatic breast cancer (mBC) treated with eribulin (E) versus other chemotherapy showed improved overall survival (OS) favoring E. Subsequent subgroup analyses, including pts with visceral metastases (VM), also showed improved OS when treated with E. Current 3rd line mBC chemotherapy options include E, gemcitabine (G) and capecitabine (C), among others. This study evaluated 1-year (yr) OS in a real world setting among mBC pts with VM treated with E, G, or C in a US cancer center network. Methods This retrospective study investigated pts with mBC with biopsy proven VM (liver and/or lung), treated with E, G, or C in 3rd line chemotherapy from 1/1/2012 to 11/1/2018. Electronic health records and cancer registry data were used to detect differences in OS (number of mons from start of 3rd line until death). Univariate and multivariate analyses of 1-yr survival between E, G, and C were conducted using Kaplan Meier (KM) and Cox proportional hazard (CPH) models respectively. Results Of 1,828 mBC pts, 1,417 had VM, and 443 (27.5% triple negative, 13.7% HER2+ and 51.9% ER+/PR+) received 3rd line therapy with E = 229 (51.7%), G = 134 (30.2%) or C = 80(18.1%). On average, E, G, and C pts did not differ by age, ethnicity, BMI or ECOG score (categorized as good [0-1] and poor [>2]), but E pts had higher mean income compared to G or C. 1-yr KM survival analyses included 370 pts (n = 195 E, 117 G, and 58 C) with at least 1-yr follow up. 150 patients (45% E, 33% G, and 41% C) were alive at the end of 1-yr. Survival curves between E, G, and C differed significantly (Logrank p Conclusions This real-world 1-yr survival analysis of pts with mBC and VM demonstrated significantly better OS for pts receiving E as compared to G, and a trend favoring OS for patients receiving E in comparison to C. Legal entity responsible for the study Eisai Inc. Funding Eisai Inc. Disclosure S.M. Kazmi: Speaker Bureau / Expert testimony: Eisai, Takeda, Lilly, Merck; Advisory / Consultancy: Merck, Takeda. E. Wang: Non-remunerated activity/ies, Eisai employee at the time of research: Eisai. R.S. Hauser: Research grant / Funding (institution): Eisai. P.A. Kaufman: Advisory / Consultancy, Research grant / Funding (institution), research grant support, and consulting fees: Eisai. All other authors have declared no conflicts of interest.

Parameters that regulate or affect the cell cycle or the DNA repair choice between non-homologous end-joining and homology-directed repair (HDR) are excellent targets to enhance therapeutic gene targeting. Here, we have evaluated the impact of five cell-cycle modulating drugs on targeted genome engineering mediated by DNA double-strand break (DSB)-inducing nucleases, such as zinc-finger nucleases (ZFNs). For a side-by-side comparison, we have established four reporter cell lines by integrating a mutated EGFP gene into either three transformed human cell lines or primary umbilical cord-derived mesenchymal stromal cells (UC-MSCs). After treatment with different cytostatic drugs, cells were transduced with adeno-associated virus (AAV) vectors that encode a nuclease or a repair donor to rescue EGFP expression through DSB-induced HDR. We show that transient cell-cycle arrest increased AAV transduction and AAV-mediated HDR up to six-fold in human cell lines and ten-fold in UC-MSCs, respectively. Targeted gene correction was observed in up to 34% of transduced cells. Both the absolute and the relative gene-targeting frequencies were dependent on the cell type, the cytostatic drug, the vector dose, and the nuclease. Treatment of cells with the cyclin-dependent kinase inhibitor indirubin-3'-monoxime was especially promising as this compound combined high stimulatory effects with minimal cytotoxicity. In conclusion, indirubin-3'-monoxime significantly improved AAV transduction and the efficiency of AAV/ZFN-mediated gene targeting and may thus represent a promising compound to enhance DSB-mediated genome engineering in human stem cells, such as UC-MSCs, which hold great promise for future clinical applications.

Introduction Reducing racial health disparities is often stated as a population health goal, but specific targets for such improvement are seldom set. It is often assumed that improving overall health outcomes will be linked to disparity reduction, but this is not necessarily the case. Methods We compared the annual change from 1999 through 2013 in combined-race (black and white) mortality with the annual change in absolute and relative racial mortality disparities for US states. Results Median annual improvement in combined-race mortality was 1.08% per year. Annual overall mortality rate reductions ranged from 0.24% per year in Oklahoma to 1.83% per year in Maryland. For disparities, the median for the black–white absolute gap was 3.60% per year, and the median for the relative black-to-white ratio was 1.19% per year. There was no significant correlation between the combined-race measure and either the absolute (0.03) or relative disparity measure reductions (−0.17). Conclusion For mortality in US states over a recent period, improvement in the population mean and disparity reduction do not usually occur together. The disparity reduction rates observed may provide realistic guidance for public and private policy makers in setting goals for reducing population health disparity and creating investment priorities. As a starting point for discussion, the observed national median annual percentage improvement of 1.1 per year combined, 3.6% per year absolute gap reduction, and 1.2% per year relative gap reduction would be modest and reasonable goals.

e16550Background: Targeted therapy is widely used as 1st and 2nd line treatment in metastatic renal cell carcinoma (mRCC). This study assessed the impact of disease progression (DP) on patient repo...

e16571Background: As new agents receive approval for the treatment of patients with metastatic renal cell carcinoma (mRCC), it is important to understand the changing treatment landscape in the rea...

BACKGROUND AND OBJECTIVES: Youth who are homeless with adult family members comprise 37% of the US homeless population, yet mental health among this group has not yet been well described. We aimed to compare the risk of suicidality, and factors that may protect against it, between family-homeless and nonhomeless youth. METHODS: We used cross-sectional data, representing 62 034 eighth- to 12th-graders, to estimate the adjusted odds ratio (aOR) of emotional distress, self-injury, suicidal ideation, and attempted suicide in the past 12 months for youth who experienced family homelessness in the past 12 months compared with housed youth, controlling for covariates. We then tested whether developmental assets moderated these outcomes. RESULTS: Four percent ( n = 4594) of youth (mean age 14.9 years) were homeless with an adult family member. Among these, 29.1% ( n = 1317; aOR: 2.52, 95% confidence interval [CI] 2.34–2.69) reported self-injury, 21% ( n = 940; aOR: 2.30, 95% CI: 2.14–2.48) reported suicidal ideation, and 9.3% ( n = 416; aOR: 3.24, 95% CI: 2.91–3.60) reported suicide attempts. Developmental assets decreased the odds of these outcomes for all youth but were less protective for homeless youth. CONCLUSIONS: Youth experiencing recent family homelessness are at higher risk of suicidality than their nonhomeless peers, suggesting homelessness itself as a marker of risk. Factors that protect emotional health are less impactful among youth experiencing recent family homelessness. Thus, interventions among homeless youth may need to address social determinants of health such as stable housing and adversity in addition to developmental assets.

Objective The present study examines whether the prevalence of vulnerable peers in school protects the emotional health of youth who are lesbian, gay, bisexual or questioning (LGBQ), overweight, or have a disability, and if the adverse emotional effects of bullying victimization are mitigated by the presence of these peers. Methods Survey data come from a large school-based sample of adolescents attending 505 schools. The primary independent variable was the percent of students in school with each vulnerability characteristic. Multilevel logistic regression models estimated the odds of internalizing problems, self-harm, suicidal ideation and suicide attempts among students who were LGBQ, overweight or had a disability. Cross-level interaction terms were added to determine if the association between being victimized and emotional distress was moderated by the presence of vulnerable peers. Results Greater presence of similar students was, on average, protective against emotional distress for LGBQ girls and overweight boys. In contrast, greater presence of students with a disability was, on average, a risk factor among girls with a disability. Several tests of effect modification indicated that odds of emotional distress for those who had been victimized were lower in schools with a higher proportion of vulnerable youth. Conclusions The presence of a similar peer group may increase the likelihood that a bystander or witness to bullying will react in a helpful way. School personnel, health care providers and other youth service professionals should inquire about social relationships at school, including experiences of harassment and perceptions of peer support, to buffer negative experiences.

The purpose of this study was to determine the relationships among preconception stressful life events (PSLEs), women's alcohol and tobacco use before and during pregnancy, and infant birthweight. Data were from the Early Childhood Longitudinal Study-Birth Cohort (n = 9,350). Data were collected in 2001. Exposure to PSLEs was defined by indications of death of a parent, spouse, or previous live born child; divorce or marital separation; or fertility problems prior to conception. Survey data determined alcohol and tobacco usage during the 3 months prior to and in the final 3 months of pregnancy. We used staged multivariable logistic regression to estimate the effects of women's substance use and PSLEs on the risk of having a very low (

The purpose of the study was to understand the association between stressful life events prior to conception (PSLEs) and women's alcohol and tobacco use prior to and during pregnancy, and the continuation of such use through pregnancy. Data were from the Early Childhood Longitudinal Study-Birth Cohort (n = 9,350). Data were collected in 2001. Exposure to PSLEs was defined by indications of death of a parent, spouse, or previous live born child, divorce or marital separation, or fertility problems prior to conception. Survey data determined alcohol and tobacco usage during the 3 months prior to and in the final 3 months of pregnancy. Weighted regressions estimated the effect of PSLEs on alcohol and tobacco use at each time point and on the continuation of use, adjusting for confounders. Experiencing any PSLE increased the odds of tobacco use prior to (adjusted odds ratio [AOR] 1.52, 95 % confidence interval (CI) 1.23-1.87) and during pregnancy (AOR 1.57, 95 % CI 1.19-2.07). Women exposed to PSLEs smoked nearly five additional packs of cigarettes in the 3 months prior to pregnancy (97 cigarettes, p = 0.011) and consumed 0.31 additional alcoholic drinks during the last 3 months of pregnancy than unexposed women. PSLEs are associated with tobacco use before pregnancy and alcohol and tobacco use during pregnancy. Alcohol and tobacco screening and cessation services should be implemented prior to and during pregnancy, especially for women who have experienced PSLEs.

Objectives. We sought to determine whether the effects of preconception stressful life events (PSLEs) on birth weight differed by neighborhood disadvantage. Methods. We drew our data from the Early Childhood Longitudinal Study, Birth Cohort (2001–2002; n = 9300). We created a neighborhood disadvantage index (NDI) using county-level data from the 2000 US Census. We grouped the NDI into tertiles that represented advantaged, middle advantaged, and disadvantaged neighborhoods. Stratified multinomial logistic regressions estimated the effect of PSLEs on birth weight, controlling for confounders. Results. We found a gradient in the relationship between women’s exposure to PSLEs and having a very low birth weight (VLBW) infant by NDI tertile; the association was strongest in disadvantaged neighborhoods (adjusted odd ratio [AOR] = 1.62; 95% confidence interval [CI] = 1.04, 2.53), followed by middle (AOR = 1.39; 95% CI = 1.00, 1.93) and advantaged (AOR = 1.29; 95% CI = 0.91, 1.82) neighborhoods. We observed a similar gradient for women with chronic conditions and among minority mothers. Conclusions. Women who experienced PSLEs, who had chronic conditions, or were racial/ethnic minorities had the greatest risk of having VLBW infants if they lived in disadvantaged neighborhoods; this suggests exacerbation of risk within disadvantaged environments. Interventions to reduce rates of VLBW should focus on reducing the deleterious effects of stressors and on improving neighborhood conditions.

Background The aim of this study was to estimate the cost-effectiveness of injectable extended-release naltrexone (XR-NTX) compared with methadone maintenance and buprenorphine maintenance treatment (MMT and BMT, respectively) for adult males enrolled in treatment for opioid dependence in the United States from the perspective of state-level addiction treatment payers. Methods A Markov model with daily time cycles was used to estimate the incremental cost per opioid-free day in a simulated cohort of adult males aged 18–65 over a 6-month period from the state health program perspective. Results XR-NTX is predicted to be more effective and more costly than methadone or buprenorphine in our target population, with an incremental cost per opioid-free day gained relative to the next-most effective treatment (MMT) of $72. The cost-effectiveness of XR-NTX relative to MMT was driven by its effectiveness in deterring opioid use while receiving treatment. Conclusions XR-NTX is a cost-effective medication for treating opioid dependence if state addiction treatment payers are willing to pay at least $72 per opioid-free day.

e17589 Background: Describe the treatment patterns of patients initiated on NCCN-recommended small molecular kinase inhibitors (SMKIs) for radioiodine-refractory differentiated thyroid cancer (DTC) approved in the United States. Methods: A large national US claims database was used to identify adult patients diagnosed with thyroid cancer (≥2 non-DX medical claims, ≥ 30 days apart) from 1/1/2006 - 6/30/2016 (study period) with claims for SMKIs from 1/1/2010 - 5/31/2016. Continuous enrollment required participation in a commercial or Medicare Advantage health plan ≥3 months before and ≥1 month following index date (date of first pharmacy claim for SMKI). Line of therapy (LOT) periods were defined by receipt and timing of SMKIs. Patient follow up was earliest disenrollment, death or end of the study period. Patient characteristics and SMKI treatment patterns were described. Results: A total of 217 DTC patients were identified; 63% commercially insured and 37% Medicare Advantage. Almost half were male (48%); mean age was 61.2 years (standard deviation SD 12.5 years) and mean follow-up period was 499 days (SD 414 days). In the study period, 35% (n = 77) of patients had ≥2 LOTs and 18% (n = 39) had ≥3 LOTs. Mean treatment duration was 5.4 months (SD 6.7 mos) for LOT1, 4.9 months (SD 3.8 mos) for LOT2, and 4.2 months (SD 4.9 mo) for LOT3. During the full study period, the most used regimens were Sorafenib for both LOT1 (37%) and LOT2 (25%), pazopanib (18%) and sunitinib (18%) in LOT3. Also, in the study period, 33 patients had sorafenib in LOT1 of which 16 were treated with sorafenib again (48%) in LOT2. Post FDA approval in 2015, Lenvatinib became the predominant first-line regimen (47%, n = 29) during study period. Across all first line therapies, for those patients with ≥12 months of follow-up, 53% (n = 60) initiated LOT2. Conclusions: Sorafenib was the most common first line of therapy for DTC, with Lenvatinib adoption increasing as first-line therapy since the drug’s approval in 2015. Depending on the period evaluated, almost half to 2/3 of patients are not receiving a second line of treatment, efficacious and patient appropriate therapy is of importance in treating this rare cancer.

Macrophage-activating lipopeptide-2 (MALP-2) is a potent inducer of proinflammatory cytokine secretion by macrophages, monocytes, and dendritic cells. MALP-2 was reported to be involved in natural killer (NK) cell activation and ensuing tumor rejection. However, the mechanism of MALP-2-mediated NK cell activation remained unclear. Therefore, we studied the effects of MALP-2 on cultured human NK cells. We found that MALP-2 had no direct effect on NK cells. Instead, MALP-2 acted on monocytes and triggered the release of different molecules such as interleukin (IL)-1β, IL-6, IL-10, IL-12, IL-15, interferon gamma-induced protein (IP-10), and prostaglandin (PG)-E2. Our data show that monocyte-derived IP-10 could significantly induce NK cell cytotoxicity as long as the immunosuppression by PGE2 is specifically inhibited by cyclooxygenase (COX)-2 blockade. In summary, our results show that MALP-2-mediated stimulation of monocytes results in the production of several mediators which, depending on the prevailing conditions, affect the activity of NK cells in various ways. Hence, MALP-2 administration with concurrent blocking of COX-2 can be considered as a promising approach in MALP-2-based adjuvant tumor therapies.

Background Mesenchymal stem cells (MSCs) are increasingly considered to be used as biological immunosuppressants in hematopoietic stem cell transplantation (HSCT). In the early reconstitution phase following HSCT, natural killer (NK) cells represent the major lymphocyte population in peripheral blood and display graft-vs-leukemia (GvL) effects. The functional interactions between NK cells and MSCs have the potential to influence the leukemia relapse rate after HSCT. Until date, MSC-NK cell interaction studies are largely focussed on bone marrow derived (BM)-MSCs. Umbilical cord derived (UC)-MSCs might be an alternative source of therapeutic MSCs. Thus, we studied the interaction of UC-MSCs with unstimulated allogeneic NK cells. Results UC-MSCs could potently suppress NK cell cytotoxicity in overnight cultures via soluble factors. The main soluble immunosuppressant was identified as prostaglandin (PG)-E2. Maximal PGE2 release involved IL-1β priming of MSCs after close contact between the NK cells and UC-MSCs. Interestingly, blocking gamma-secretase activation alleviated the immunosuppression by controlling PGE2 production. IL-1 receptor activation and subsequent downstream signalling events were found to require gamma-secretase activity. Conclusion Although the role of PGE2 in NK cell-MSC has been reported, the requirement of cell-cell contact for PGE2 induced immunosuppression remained unexplained. Our findings shed light on this puzzling observation and identify new players in the NK cell-MSC crosstalk. Electronic supplementary material The online version of this article (doi:10.1186/s12964-014-0063-9) contains supplementary material, which is available to authorized users.

Human blood NK cells exert strong cytotoxicity against transformed cells and produce different cytokines and chemokines with an important role in modulating immune responses. However, the nature of NK-cell function depends on NK-cell interaction with other immune cells. One type of immune cells that communicate with NK cells are 6-sulfo LacNAc DCs (slanDCs), which comprise a major subpopulation of proinflammatory human blood DCs. In this study, we investigated the molecular mechanisms by which slanDCs interact with NK cells. Our in vitro studies demonstrate that LPS-stimulated slanDCs enhance activation and function of NK cells essentially via membrane-bound TNF-α (mTNF-α). LPS stimulation upregulates expression of mTNF-α in slanDCs, and surface TNF receptor 2 (TNFR2) is upregulated on NK cells after coincubation with slanDCs. IL-12 secreted by slanDCs increases surface expression of TNFR2 in NK cells. TNFR2 signaling in NK cells leads to activation of NF-kB, a transcription factor for cytokines such as GM-CSF. GM-CSF provided by NK cells is responsible for enhancing IL-12 secretion in slanDCs. In conclusion, TNFR2 and IL-12 signaling, which support one another, enables slanDCs to enhance NK-cell function through mTNF-α, thereby regulating immune responses.

Objectives. We determined whether and to what extent a woman’s exposure to stressful life events prior to conception (PSLEs) was associated with preterm birth and whether maternal age modified this relationship. Methods. We examined 9350 mothers and infants participating in the first wave of the Early Childhood Longitudinal Study, Birth Cohort, a nationally representative sample of US women and children born in 2001, to investigate the impact of PSLEs on preterm birth in the United States. We estimated the effect of exposure on preterm birth with weighted logistic regression, adjusting for maternal sociodemographic and health factors and stress during pregnancy. Results. Of the women examined, 10.9% had a preterm birth. In adjusted analyses, women aged 15 to 19 years who experienced any PSLE had over a 4-fold increased risk for having a preterm birth. This association differed on the basis of the timing of the PSLE. Conclusions. Findings suggest that adolescence may be a sensitive period for the risk of preterm birth among adolescents exposed to PSLEs. Clinical, programmatic, and policy interventions should address upstream PSLEs, especially for adolescents, to reduce the prevalence of preterm birth and improve maternal and child health.